Abstract Problem. The use of combination antiretroviral therapy (cART) has allowed people living with HIV (PLWH) to live longer and healthier. Nevertheless, more than half of PLWH still have varying degrees of HIV Associated Neurocognitive Disorder (HAND) despite viral suppression with cART. Longer duration of HIV infection and aging may have conjoining negative effects on cognitive function and neurodegeneration. As the PLWH are growing older, it is important to differentiate HAND from neurodegenerative diseases affecting the general aging population, such as Alzheimer's Disease (AD). Both HAND and AD might share neuropathological mechanisms, which have not been systematically studied, in PLWH during suppressive cART. Overarching Goal. To characterize the molecular signatures underlying HAND during viral suppression on cART, and describe the commonalities and differences with those molecular signatures associated with AD. Cohorts and Samples. We will use complementary and well-characterized cohorts with extensive longitudinal available clinical, neurocognitive and laboratory data from two major research programs: HIV Neurobehavioral Research Program (HNRP) and Shiley-Marcos Alzheimer's Disease Research Center (ADRC). A. HNRP: We will retrospectively include CSF and blood samples from participants who (i) had normal cognition at baseline and had incident HAND at a subsequent time-points (HAND group, n=100) and, (ii) age- matched participants who had normal cognition at baseline and did not develop HAND in any of the subsequent time-points (no-HAND group, n=100). For the HAND group, we will also evaluate samples at the time-point when HAND was first diagnosed. For subset of participants (n=20), we will include stored post- mortem brain tissue for exploratory evaluation. B. ADRC: We will retrospectively include CSF and blood samples from participants who: (i) had Mild Neurocognitive Impairment (MCI) at baseline and developed AD in the subsequent time-point (AD group, n=50) and, (ii) age-matched participants who had normal cognition during all observational time-points (control group, n=50). Brain tissue will also be available for a subset of participants (n=20) for exploratory evaluation. Approach. We propose a highly innovative approach by generating and analyzing high dimensional data focused on study objectives designed to be responsive to the parent RFA-AG-18-023. Specifically, we will generate metabolomics and lipidomics (aim 1), transcriptomics (aim 2), and we will integrate these data with relevant AD-associated genetic variants, clinical variables and measures of classical AD biomarkers (aim 3) to develop molecular interaction networks and predictive models of HAND and AD. Our study has the potential to yield highly translatable results by identifying pathways that can be targeted to improve care for both ageing HIV population and AD population. The data collected as part of this project will also lay the groundwork for future studies that can tackle a wide variety of open questions concerning aging, HIV and neurodegeneration.